Effective new cancer therapies have been developed based on agents with novel mechanisms of action that specifically target the pathophysiology of malignances. Most of these diseases exhibit a pronounced defect in normal lymphocyte cell death mechanisms due to over-expression of pro-survival proteins. It is now recognized that a critical aspect of B cell malignancy metabolism is directed at replenishing the pro-survival proteins that keep these cells from dying due to apoptosis. This is required because sequence motifs intrinsic to the primary protein structure of these pro-survival proteins, signal for the rapid turnover of these proteins (e.g. Mcl-1, XIAP). This is a hallmark of the pathophysiology of B cell malignancies. Importantly, even transient inhibition of translation rapidly diminishes these key proteins to a level that cannot prevent apoptosis. Once initiated, this lethal process is irreversible. Because normal lymphoid cells do not exhibit this dependency, it appears that CLL cells are “addicted” to the continual expression of the anti-apoptotic proteins for survival.
Pateamine A (PatA) was initially isolated from the marine sponge Mycale sp. by bioassay-guided fractionation based on its cytotoxic activity against P388 murine leukemia cells (IC50, 0.27 nmol/L). Consistent with its cytotoxicity, PatA was subsequently shown to induce apoptosis in several cancer cell lines. Des-methyl, des-amino pateamine A (DMDAPatA) is a simplified analog of the natural product that is easier to synthesize and a potent anti-proliferative agent in vitro against >30 human cancer cell lines.

PatA and DMDAPatA inhibit cap-dependent translation initiation by sequestration of eIF4A that prevents formation of the eIF4F complex, or by stalling the initiation complex on mRNA. Xenograft studies in mice showed DMDAPatA has high activity in models of human leukemia and melanoma leading to significant tumor reduction, thus demonstrating good bioavailability. The synthesis of >20 derivatives of PatA led to the identification of DMDAPatA which was also found to be significantly more stable than the natural product. Overexpression of multidrug resistant protein did not affect this activity. Importantly, DMDAPatA reduces the levels of intrinsically short-lived anti-apoptotic proteins in primary CLL cells, and initiates apoptosis. However, preliminary data on DMDAPatA suggests that it is highly protein bound in human plasma and may lack sufficient in vivo potency required for development as an effective therapeutic agent.
Although PatA and DMDAPatA appear to be attractive candidates for the development of therapeutic agents, a need exists for improved PatA derivatives having therapeutic effectiveness, low toxicity, and advantageous pharmacokinetic properties. The present invention seeks to fulfill these needs and provides further related advantages.